High-grade gliomas are devastating tumors with poor prognoses and limited treatment options. Therapy resistance is a great obstacle to glioma treatment and patient survival is generally measured in months. A thorough knowledge of the genetic basis of glioma initiation, progression and therapy resistance will be important for developing better therapies for the disease. We have been using the Sleeping Beauty (SB) transposon system as an insertional mutagenesis technology for cancer gene discovery in sarcomas, hematopoietic tumors and prostate cancer in mouse models of human cancer. Recently, we have discovered that although most mice suffering whole body mobilization of SB transposons develop hematopoietic disease, some also develop high-grade gliomas. We hypothesize that these SB-induced gliomas can be used to identify new genes involved in gliomagenesis. Furthermore, we propose to modify the SB technology to limit mutagenesis to glioma-initiating cells to generate a new pre- clinical murine model for studying glioma formation and therapy response. We will also use the SB technology as a mutagen in cell culture models to study the genetic basis of therapy resistance. Cell culture models will also be used to validate the role of genes identified by SB in glioma formation and therapy resistance. In summary, the SB system holds great promise to study the genetics of gliomagenesis and therapy resistance. PUBLIC HEALTH RELEVANCE: High-grade gliomas are devastating tumors with limited treatment options and high rates of therapy resistance. We propose here to use the Sleeping Beauty transposon technology to identify new genes involved in glioma formation and therapy resistance. A thorough understanding of the genetic basis of glioma initiation and progression is crucial for designing new and better therapies for the disease.